This invention relates to pharmaceutical compositions comprising small particle size (smaller than about 80 mesh U.S. standard) psyllium husk and cholestyramine having improved cholestyramine aesthetics, and a method for treating hypercholesterolemia by administering said pharmaceutical composition.
High blood cholesterol levels are associated with life threatening cardiac diseases. A drug of choice in the treatment of such disorders is cholestyramine resin, which is known as a basic anion exchange resin. Cholestyramine helps to lower blood cholesterol levels apparently by binding to bile acids in the intestine. It is believed that this in turn causes an increase in hepatic metabolism of cholesterol to replenish the bile acids lost to complexation with the cholestyramine.
Cholestyramine is usually dosed using from four to thirty-two grams, given once daily or divided into two, three, or four equal intervals. At the present time a commercial cholestyramine product, Questran.RTM. (manufactured by the Mead Johnson division of Bristol-Myers Company) is sold in a four grams unit dose powder packet or in bulk powder, and as Cholybars manufactured by Parke Davis) wherein one chewable bar contains four grams of cholestyramine. [Physicians Desk Reference, 44th Edition, pages 726-729 and 1595-1597 (1990).]
While the benefits of cholestyramine are well known and appreciated, the aesthetics (e.g., mouthfeel; taste; throat sticking) are considered by many users of cholestyramine to be very unpleasant. Obviously, poor aesthetics raise concern about how closely patients comply with any treatment regimen using cholestyramine. The unpleasant mouthfeel of cholestyramine is frequently described as a sandy, gritty texture which tends to stick to the back of the mouth and throat upon ingestion and which leaves an unpleasant fishy taste in the mouth.
Several attempts have been made to improve the palatability of cholestyramine. Patents which disclose such attempts include: East German Patent DD 249,634 published Sep. 16, 1987 by V&B Chemukombinat Bitterfeld (discloses grinding a basic anionic exchanger such as cholestyramine in a wet state and spraying on an aqueous solution of pectin during drying); Great Britain Patent Specification Number 1,446,352, published Aug. 18, 1976 by Merck & Co., Inc. (discloses an oral pharmaceutical composition in liquid form comprising a coacervate of a hydrophilic colloid of a cellulose derivative, such as sodium carboxymethyl cellulose, and cholestyramine); French Medical Patent 6,888 M published Jun. 4, 1964 by Mead Johnson & Company (discloses dry mixing acacia gum with cholestyramine resin to aid in making the extreme astringency of cholestyramine disappear); U.S. Pat. No. 4,895,723, issued to Amer et al. Jan. 23, 1990 (describes orally ingestible compositions for reduction of blood cholesterol levels comprising cholestyramine and a water-soluble carbohydrate syrup such as high fructose corn syrup or a liquid alcohol polyol humectant such as glycerine); U.S. Pat. No. 4,843,098, issued to Shaw et al. Jun. 27, 1989, U.S. Pat. No. 4,818,539, issued to Shaw et al. Apr. 4, 1989, and U.S. Pat. No. 4,790,991, issued to Shaw et al. Dec. 13, 1989, divisions of U.S. Pat. No. 4,747,881, issued to Shaw et al. May 31, 1988 (relating to preswelled substantially anhydrous hydrocolloid aggregate such as carboxymethyl cellulose with a size range of about 4 to about 70 U.S. mesh, and a substrate comprising dietary fiber and/or drug, such as cholestyramine); U.S. Pat. No. 4,778,676, issued to Yang et al. Oct. 18, 1988 (discloses a chewable delivery system for actives comprising an active, such as cholestyramine, pre-coated with at least one material selected from the group consisting of lecithin, polyoxyalkenes having chain lengths of about four carbons or less, glycerides having a melting point of 100.degree. C. or less, polyalkylene glycols having a molecular weight of 3,700 or less, synthetic and natural waxes and mixtures thereof, and a confectionery matrix comprising a binder system of gelatin and a humectant material); U.S. Pat. No. 3,974,272, issued to Pollt et al. Aug. 10, 1976 (discloses a palatable oral coacervate composition containing cholestyramine and a Modified Gum selected from the group consisting of hydrophillic colloid of cellulosive material and charged anionic gum in an aqueous medium); and U.S. Pat. No. 3,499,960, issued to Macek et al. (discloses coating the cholestyramine particles with an acrylic polymer crosslinked with allylsucrose).
Other publications relating to therapeutic use of 10 cholestyramine or psyllium include the following. European Patent Application Publication No. 323,666, published Jul. 12, 1989 by The Procter & Gamble Company. This patent describes methods and compositions for reducing blood cholesterol levels by oral administration of psyllium and cholestyramine, optionally in combination with polyol polyesters. It is also stated therein that "cholestyramine resin, administered orally, has sometimes been associated with constipation and preparations containing cholestyramine often have an unpleasant sandy or gritty quality. Advantageously, these problems associated with cholestyramine are alleviated when the psyllium and/or psyllium plus optional polyol polyesters are employed therewith."
U.S. Pat. No. 4,824,672, issued to Day et al. Apr. 25, 1989, discloses an orally utilizable pharmaceutical composition comprising gel-forming fiber (such as guar gum, psyllium seed, pectin, glucomannan, oat and barley) and a mineral salt (such as calcium carbonate, magnesium carbonate, or potassium carbonate) said to be administered to humans to reduce serum cholesterol levels.
Management of Hvpercholesterolemia, Approach to Diet and Drug Therapy, Stein, The American Journal of Medicine, Vol. 87(4A) (1989) advises patients who experience constipation from the use of cholestyramine or colestipol (bile acid sequestrants used to decrease blood cholesterol levels) to take a bulk laxative, such as psyllium fiber, with the evening dose of sequestrant if other dietary changes do not alleviate the problem of constipation.
The Effect of Psyllium Hydrocolloid and Cholestyramine on Hepatic Bile Lipid Composition in Man, Behrer et al., Henry Ford Hospital Medical Journal, Vol. 21(1) (1973), examined the effects of psyllium hydrocolloid and of cholestryramine on the total cholesterol, total phospholipid, total bile salt, cholate, chenodeoxycholate, and deoxycholate concentrations of 6 post-cholecystectomy patients.
Although there has been much research devoted to cholestyramine and to improving the aesthetics of cholestyramine, there continues to be a need for improved products containing cholestyramine. In the present invention, it has surprisingly been discovered that small particle size psyllium husk, smaller than that previously commercially available in certain laxative products, when used in combination with cholestyramine, improves the aesthetics of the cholestyramine. The object of the present invention is therefore to provide a pharmaceutical composition comprising small particle size psyllium husk and cholestyramine with improved aesthetics, including palatability and/or mouthfeel. A further object of this invention is to provide a method for improving the palatability and overall mouthfeel of cholestyramine and a method for enhancing compliance and convenience with a treatment regimen for treating hypercholesterolemia by administering to humans a pharmaceutical composition comprising small particle size psyllium husk and cholestyramine. An object of the present invention is also to provide a method for treating hypercholesterolemia by administering to humans a pharmaceutical composition comprising small particle size psyllium husk and cholestyramine. Another object of the present invention is to provide a bowel normalizing benefit to patients being treated for hypercholesterolemia through administration of a pharmaceutical composition comprising small particle size psyllium husk and cholestyramine.
These and other objects of the present invention will become readily apparent from the detailed description which follows.
All percentages and ratios used herein are by weight and all measurements are made at 25.degree. C. unless otherwise specified. Screen mesh sizes used herein are based on U.S. standards.